The clinical management of hepatic sarcoidosis: A systematic review

Abstract Background Hepatic sarcoidosis is an uncommon clinical condition in which clear recommendations are lacking in its treatment. We aimed to review systematically the literature on hepatic sarcoidosis treatment to guide clinicians. Methods Using MEDLINE, PubMed, CINAHL, Cochrane Library, and Google Scholar databases, we searched original articles on clinical studies reporting the outcome of adult hepatic sarcoidosis patients following treatment with various pharmacological agents. The primary end point was focused on assessing symptomatic relief and biochemical improvement posttreatment. Results Out of 614 retrieved references, 34 published studies were eligible, providing data for a total of 268 patients with hepatic sarcoidosis. First‐line therapy with corticosteroids alone was reported in 187 patients, whilst ursodeoxycholic acid (UDCA) was used in 40 patients. Symptomatic and biochemical responses were reported among 113(60.4%) and 80(42.8%) cases of corticosteroids respectively, whereas UDCA showed a complete response in 23(57.5%) patients. Second‐line therapy was used in steroid‐refractory cases, with most cases being reported for azathioprine (n = 32) and methotrexate (n = 28). Notably, 15(46.9%) and 11(39.2%) patients showed both clinical and biochemical responses respectively. Biological therapy including anti‐tumor necrosis factor (anti‐TNF) was used as third line therapy in twelve cases with a 72.7% symptomatic and biochemical response rate each. Conclusion The quality of evidence for the treatment of hepatic sarcoidosis was poor. Nevertheless, it appears that corticosteroid or UDCA may be utilized as first‐line therapy. For cases that are refractory to corticosteroids, steroid‐sparing immunosuppressive agents and anti‐TNF have shown some promising results, but further high‐quality studies are required.


Introduction
Sarcoidosis is a rare multisystem disorder of unknown etiology.It is characterized by the presence of noncaseating granuloma histologically.2][3] Extrapulmonary diseases are often seen as part of systemic sarcoidosis with involvement of most organs particularly skin, eyes, liver, spleen, cardiac, salivary gland, and bone marrow. 4Although hepatic involvement in systemic sarcoidosis has been reported in 50-80% of autopsy studies, 2,4-6 isolated hepatic sarcoid is rare.Furthermore, most patients with hepatic sarcoidosis are asymptomatic or have mild disease, 2,7,8 less than 1% of patients progress to severe cholestatic jaundice, portal hypertension, Budd-Chiari syndrome, cirrhosis as well as end-stage liver disease which requires liver transplant. 5,8,9here has been considerable progress in basic research and the diagnosis of hepatic sarcoidosis over the past few years.
0][11] Corticosteroids remain the mainstay of treatment despite a lack of prospective controlled studies. 6Failure or adverse effects of corticosteroids leads to the initiation of various other treatments as second-line therapy to achieve remission, namely methotrexate, azathioprine, and tumor necrosis factor (TNF) inhibitors such as infliximab. 2,5,6,9,12However, the evidence for the timing and the choice of second-line therapy is lacking.
In lieu of the ambiguity of the management of hepatic sarcoidosis, we conducted a systematic review of the literature on pharmacological therapy in hepatic sarcoidosis.The aim of this study was to identify available treatment strategies for patients with hepatic sarcoidosis, the appropriate timing to initiate treatment and to summarize their efficacy and outcomes.
Selection process.Following the search, all identified records were loaded into EndNote X20 (Clarivate Analytics, Philadelphia, PA, USA) and duplicates were removed.Two reviewers (RP and VK) worked in pairs to independently screen titles and abstracts, followed by full-text papers using the inclusion and exclusion criteria.We included all studies with the following inclusion criteria: (a) any clinical study design reporting the outcome of human adult hepatic sarcoidosis patients, that is, case reports, case series, case-control studies or randomized clinical trials, (b) human adult hepatic sarcoidosis cases confirmed by histology/ liver biopsy, (c) intervention with any pharmacological agent, (d) either clinical symptoms, biochemical or histological response to treatment.There were no language restrictions and the only exclusion criteria were animal studies.Disagreements were resolved by discussion with the review team (SM) as necessary.Outcome measures.The primary end point of this systematic review was focused on assessing symptomatic relief and biochemical improvement posttreatment.All patients that been initiated on treatment will be evaluated base on symptom resolution and improvement in liver function test.With regard to biochemical improvement, we defined treatment response as follows: Complete response.It was defined as the normalization of liver parameters at the end of treatment.
Partial response.Biochemical improvement in liver indices but without liver enzymes falling within the normal range was observed.

Results
Description of selected studies.A total of 614 references were retrieved from PubMed, Embase, and Cochrane Library databases.After abstract review and full-text assessment, 34 published studies were selected (Fig. 1).Authors, study design, diagnostic criteria, inclusion and exclusion criteria, and sample size are summarized in Table 1.Notably, 24 (70%) of the selected studies were case reports, whilst 10 were case series.No prospective studies, nor randomized control trials were retrieved.
Quantitative analysis Baseline characteristics.Main baseline patient characteristics, including average age, ethnicity, clinical outcomes, and treatment, have been summarized in Table 2.The selected studies included 273 patients diagnosed either as primary disease or extra manifestation of other primary organ involvement.A bimodal pattern was observed with early peak at the age of 20-40 years and a later peak at 50-70 years old.The follow-up ranged from 2 months to a period of 11 years in one study.The most common symptom reported was abdominal pain, particularly over the right upper quadrant, stated in 15 studies.This was followed by weight loss, reported in 14 studies.Fever, fatigue, and jaundice were equally reported in nine studies.Isolated hepatic sarcoidosis was discussed only in five studies.Pulmonary disease was the commonest extrahepatic manifestation, reported in 18 studies, followed by ocular ( 8), lymphatic ( 6), cutaneous (6), spleen (5), and cardiac (5).

Treatment regimens
First-line therapy.Among 268 patients, 187 were treated with corticosteroids as first-line therapy.Ursodeoxycholic acid (UDCA) had additionally been administered in 40 patients as first-line therapy either as a single agent or in combination with corticosteroids.Both regimens are listed in Table 2.The most common type of corticosteroid used was prednisolone within a dose ranging from 20 to 60 mg/day, tapered every 6-8 weeks over a 6-month period.5][16][17][18] In one study, budesonide with a dosing of 3 mg twice daily was used.However, data on the duration of maintenance doses were unavailable. 19With regard to UDCA, the dosage that was prescribed ranged from 10 to 15 mg/kg or 300 mg twice daily.For symptom improvement, 113 (60.2%) showed symptom resolution post-treatment with corticosteroids in 23 studies.A partial response or no response was shown for corticosteroids in the remaining 10 studies (n = 74, 39.8%).With regard to biochemical response, 80 (43%) patients showed significant improvement posttreatment with corticosteroids in 18 studies.There was either a partial (n = 11, 5.9%) or no response (n = 57, 30.6%) in the remaining 12 studies.UDCA had shown a complete response (clinically and biochemically) in 23 (57.5%) patients, in five out of eight studies. 15,20,21Bakker et al. in fact reported that UDCA was superior to corticosteroids in treatment response, especially with regard to biochemical resolution. 22cond-line therapy.The steroid-sparing immunosuppressive agents used as second-or third-line therapy included azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, chlorambucil, infliximab and adalimumab.The number of cases utilizing second-line agents were as follows: azathioprine n = 32, methotrexate n = 28, mycophenolate mofetil n = 2, cyclophosphamide n = 2 and chlorambucil n = 1.None of the studies reported in detail regarding the dosage of The management of hepatic sarcoidosis RP Sinnanaidu et al.  immunosuppressive agents.Only one study suggested that the dose of azathioprine should be initiated at 25 mg /day and to adjust accordingly based on response.Second-line therapy was usually initiated due to failure of first-line treatment or as a steroid-refractory agent.Among six studies which utilized azathioprine, a total of 20(62.5%)patients showed either clinical or biochemical improvement.Both biochemical and symptomatic improvement were observed in 15 patients (five studies), 8,11,15,23,24 including histological improvement in one study 24 and two studies only showed biochemical resolution. 15,20No improvement with azathioprine was only shown in one study (n = 1, 3.1%). 14ethotrexate was the next most common second-line agent utilized in four studies.Clinical and biochemical improvement was reported in three studies (n = 11.,39.2%), 8,11,25whilst one study (n = 3, 10.7%)only had biochemistry resolution. 20Progression to cirrhosis was reported in a single case report, despite on both prednisolone and methotrexate therapy. 26oth AZA and MTX have the potential for drug-induced liver injury (DILI).However, the rate of DILI appeared to be low with only two cases reported by Graf et al., whereby AZA and MTX had to be discontinued due to hepatotoxicity effect. 20ther steroid-sparing immunosuppressive therapy that have been reported in hepatic sarcoidosis include mycophenolate mofetil [MMF] and chlorambucil, but the case numbers were low.MMF was administered in only two patients in two different studies after a failure of corticosteroids, with improvement in biochemistry and symptoms. 20,24Similarly, Chlorambucil resulted in the resolution of symptoms and liver function in a single case reported by Israel. 25 Third-line therapy.The number of cases utilizing third line agents were as follows: Anti-tumor necrosis factor (anti-TNF) (Infliximab) n = 11, Adalimumab n = 1.Infliximab was started in two patients at a dose of 5 mg/kg @ 0, 2,6 weeks then at every 6 week interval. 14,208 patients on Infliximab have showed both clinical and biochemical improvement.In a single case report by Watanabe et al., adalimumab was added following a partial response to corticosteroids.There was biochemical improvement with normalization of liver function and significant improvement on imaging.This effect continued for up to 2 years of follow-up.
Figure 2 Graphical summary of treatment efficacy for various drugs in hepatic sarcoidosis.

Discussion
This systematic review has highlighted that most of the available published data on the treatment of hepatic sarcoid have been based on case reports, case series, expert opinions and extrapolation from the pulmonary sarcoidosis literature.Despite this low quality evidence data, it can be summarized that corticosteroids are the main first-line treatment in hepatic sarcoidosis.8][39][40][41][42][43][44] In our review, some of the studies used dosages of 0.5 mg to 1 mg/kg/day, [45][46][47] and none of the studies reported a prednisolone dose of greater than 1 mg/kg/day.Two review articles suggested a time frame of 4-6 weeks for initial duration of treatment, and subsequently to taper off prednisolone 5-10 mg every 4-8 weeks. 5,12,48,49The lowest effective steroid dose was maintained for long-term treatment in most studies, 48 provided there was a good initial response.Despite its efficacy, the prolonged use of corticosteroids has to be balanced with wellknown adverse effects of weight gain, hyperglycaemia, and increased risk of infections, gastrointestinal bleeding, and metabolic bone disease. 9,50 few studies have shown that UDCA may be effective in hepatic sarcoidosis, but mainly in patients with cholestasis or a predominant symptom of pruritus.The recommended dosage of 10 mg/kg/day used in most of the reported studies 27,30,51,52 demonstrated improvement in liver biochemistry and symptoms of cholestasis, particularly pruritus.12,45,51 Although the patients included in this systematic review did not undergo repeated biopsy posttreatment, it has been suggested that UDCA does not impede histological progression of the disease.9,27 For cases which were refractory to corticosteroids or needed longer term immunosuppression, the available studies appear to favor azathioprine mostly, followed by methotrexate.
However, the potential risk of hepatotoxicity from MTX may limit its utility in hepatic sarcoidosis. 53The efficacy for other immune-suppressants such as MMF and chlorambucil have only been reported in very small number of patients (n < 5) and hence remain uncertain.
Tumor necrosis factor (TNF) alpha is implicated in the pathogenesis of sarcoidosis by inducing inflammation and granuloma formation. 54Thus, TNF inhibitors may prevent granuloma pathogenesis by binding to TNF-alpha and inhibiting its activity. 5,55In this review, the few studies exploring anti-TNF, which includes infliximab or adalimumab therapy, have suggested that they may be helpful in liver biochemistry improvement, but the small number of cases (n = 11) was not sufficient to demonstrate a significant improvement.
This systematic review has highlighted the lack of good quality evidence for the treatment of hepatic sarcoidosis.There were no randomized controlled trials nor prospective studies which have been published to date.Most of the data available were from case reports or case series, which might have led to a publication bias.However, due to the lack of randomized controlled trials nor prospective studies in this area, we have decided to include such studies.Another limitation was the heterogeneity of the endpoints, which did not allow for comparison between outcomes.There is no standardized method to evaluate outcomes, such as posttreatment liver biopsy, as well as a standardized definition to conclude treatment response.Furthermore, the duration of treatment varied widely from one study to another.Moreover, data on adverse drug events were not provided in all studies, making safety comparisons between corticosteroids and steroid-sparing immunosuppressants difficult.Lastly, there may have been some publication bias as some cases of isolated hepatic sarcoidosis do not develop symptoms nor serious sequelae.
Taking into consideration of these limitations in the context of a rare disease, with the available data, we suggest the following as a reasonable approach to the treatment of hepatic sarcoidosis: an early corticosteroid treatment at 0.5 to 1 mg/kg/ day with a 3 to 6 months tapering scheme in cases of clinical and biochemical/ imaging remission, and an adjunctive therapy by a steroid sparing agent such as AZA and MTX at usual doses.(Fig. 3).
Patients' follow-up should be based on their initial presentation (evidence of cirrhosis, fibrosis, or liver failure).Despite the interest in TNF-α antagonists as a potential treatment modality in hepatic sarcoidosis, the published evidence in the literature remains limited.We conclude that further studies with homogenous groups, comparisons between the different treatments' schemes and with reproducible strong endpoints are needed.

RP
Sinnanaidu et al.The management of hepatic sarcoidosis

Figure 3
Figure 3 Proposed treatment algorithm for hepatic sarcoidosis, based on available data from the current literature.

Table 1
Summary of clinical reports included in the systematic review

Table 2
Summary of treatment and outcomes of patients with hepatic sarcoidosis from clinical reports